US2024277747A1PendingUtilityA1
Compounds for Treating Genetic Diseases
Est. expiryMay 28, 2041(~14.9 yrs left)· nominal 20-yr term from priority
Inventors:Roger B. ClarkYoshitaka IchikawaWesley Francis AustinShuhao ShiWenying WangXiben LiIvan Jewett
A61P 11/00A61P 17/00C07H 17/08A61K 45/06A61K 31/7052
45
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Claims
Abstract
Provided are 13-membered ribosome targeting compounds that can be used to treat genetic diseases, including genetic diseases that are associated with a premature termination codon mutation or other nonsense mutation. The compounds can induce and/or promote readthrough of the premature termination codon mutation. Also provided are pharmaceutical compositions containing the compounds, methods of using the compounds and processes for making the compounds.
Claims
exact text as granted — not AI-modified1 . A method for treating a subject having a genetic disease comprising:
administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
one of R 2a and R 2b is selected from the group consisting of H, halo, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, and optionally substituted C 2-10 alkenyl, wherein C 1-10 alkyl, C 1-10 alkoxy, and C 2-10 alkenyl are optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl; and the other of R 2a and R 2b is selected from the group consisting of halo, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, and optionally substituted C 2-10 alkenyl, wherein C 1-10 alkyl, C 1-10 alkoxy, and C 2-10 alkenyl are optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, alkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;
each of R 4a and R 4b is independently selected from the group consisting of H and optionally substituted C 1-10 alkyl;
R 5 is selected from the group consisting of H, a hydroxyl protecting group, and
R 6a is optionally substituted C 1-10 alkyl;
R 6b is H, C 1-10 alkyl, C 1-10 hydroxyalkyl, allyl, haloalkyl, aryl, heteroalkenyl, heterocycloalkyl, or heteroaryl, any of which can be optionally substituted with one or more groups selected from the group consisting of halo, aryl, amino, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heteroaryl;
R 8a and R 8b are each independently selected from the group consisting of H and optionally substituted C 1-10 alkyl;
R 9a is selected from the group consisting of H, optionally substituted C 1-10 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-cyclolkyl, C(═O)C 1-6 alkylene-cycloalkyl, C(═O)cycloalkyl, C(═O)heterocycloalkyl, C(═O)aryl, C(═O)heteroaryl or C(═O)NH-aryl;
one of R 10a and R 10b is selected from the group consisting of H and optionally substituted C 1-10 alkyl, and the other of R 10a and R 10b is
L a -L b -L c -L d wherein:
L a is C 2-6 alkyenylene or C 1-6 alkylene, wherein one methylene unit of C 1-6 alkylene may be replaced by oxo
L b is absent, or is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
L c is absent or is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N—C 1-6 alkyl, N—C 1-6 cycloalkyl, —NH—C 1-6 alkylene, —N(C 1-6 alkyl)-C 1-6 alkylene, —NH—C 1-6 alkylene-heteroarylene, —N—C 1-6 alkylene-cycloalkyl, N—C 1-6 alkylene-heterocycloalkyl, N—C 1-6 alkylene-aryl, N—C 1-6 alkylene-heteroaryl, C(═O), C(═O)O—, OC(O)—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene, N(C 1-6 alkyl)-C(═O)—C 1-6 alkylene, SO 2 , SO 2 NH, SO 2 N—C 1-6 alkyl, SO 2 N—(C 1-6 alkyl)-(C 1-6 alkylene), OC(═O)—NH, OC(═O)—N-alkyl, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH—(C 1-6 alkylene), SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl),
L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted benzyl; and
R 11a and R 11b are each independently selected from the group consisting of —H and optionally substituted C 1-10 alkyl;
wherein “ ” indicates a point of attachment.
2 . The method of claim 1 , wherein the compound of formula I is a compound of formula IH
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 2 , wherein R 10b , R 11a , and R 11b are each independently H or methyl.
4 . The method of claim 2 , wherein R 9a is —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(═O)—NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe, or CH 2 CH 2 OH,
5 . The compound of claim 2 , wherein L a of -L a -L b -L c -L d is C 2-6 alkenylene; L b and L c are absent, and L d is H.
6 . The method of claim 5 , wherein L a is —CH 2 ═CH 2 —, L b and L c are absent, and L d is H.
7 . The method of claim 2 , wherein L a is C 1-6 alkylene selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, and —CH 2 CH 2 CH 2 CH 2 —, wherein one methylene unit of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 — can optionally be replaced by oxo (C═O).
8 . The method of claim 7 , wherein L a is CH 2 or oxo (C═O); L b is absent; L c is CO, C(═O)NH—C 1-6 alkylene, —NH—C 1-6 alkylene, or N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, or N(C 1-6 alkyl) 2 .
9 . The method of claim 2 , wherein:
L a is CH 2 or oxo; L b is optionally substituted cycloalkyl or heterocycloalkyl selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, any of which may be optionally substituted; L c is absent or is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N—C 1-6 alkyl, N—C 1-6 cycloalkyl, —NH—C 1-6 alkylene, —N(C 1-6 alkyl)-C 1-6 alkylene, —N—C 1-6 alkylene-cycloalkyl, N—C 1-6 alkylene-heterocycloalkyl, N—C 1-6 alkylene-aryl, N—C 1-6 alkylene-heteroaryl, C(═O), C(═O)O—, OC(O)—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene, SO 2 , SO 2 NH, SO 2 N—C 1-6 alkyl, OC(═O)—NH, OC(═O)—N-alkyl, N(C 1-6 alkyl)-C(═O)—C 1-6 alkylene, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH—(C 1-6 alkylene), SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl),
and
L d is H, —OH, C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, or optionally substituted heteroaryl.
10 . The method of claim 9 , wherein:
L a is CH 2 or C(═O); L b is azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, or morpholinyl; L c is absent or is C 1-6 alkylene, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, —OH, C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
11 . The method of claim 9 , wherein:
L a is CH 2 or oxo; L b is piperidinyl, piperazinyl, pyrrolidinyl, or morpholinyl; L c is C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, methyl, ethyl, isopropyl, isobutyl, t-butyl, triofluoromethyl, hydroxy, methoxy, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
12 . The method of claim 9 , wherein:
L a L b is
L c is absent, and L d is H;
L a L b is
L c is absent, and L d is H; or
L a L b is
L c is absent, and L d is H.
13 . The method of claim 9 , wherein:
L a L b is
L c is absent or is CH 2 , CH 2 CH 2 , CHCH 3 , CH 2 CHCH 3 , C(CH 3 ) 2 ; and
L d is H, —OH, —OMe, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, trifluormethyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
14 . The method of claim 9 , wherein:
L a L b is
L c is oxo; and
L d is H, methyl,ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, phenyl, trifluormethyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
15 . The method of claim 9 , wherein:
L a L b is
L c is SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N—C 1-6 alkyl, SO 2 N—(C 1-6 alkyl)(C 1-6 alkylene); and
L d is H, methyl, ethyl, propyl, isopropyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl,
16 . The method of claim 9 , wherein:
L a L b is
L c is absent or is C 1-6 alkylene, C(═O), C(═O)O, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene; and
L d is H, hydroxyl, C 1-6 alkyl, alkoxy, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl.
17 . The method of claim 9 , wherein:
L a is CH 2 or oxo; L b is cyclobutyl; L c is absent or is —NH—C 1-6 alkylene, or N(C 1-6 alkyl)-C 1-6 alkylene; and L d is H, methyl, ethyl, isopropyl, cyclopropyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
18 . The compound of claim 9 , wherein:
L a L b is
L c is NHCH 2 —, N(Me)CH 2 —, N(Et)CH 2 —, N(iPr)CH 2 —, N(isobutyl)CH 2 —,; and
L d is H or cyclopropyl.
19 . The method of claim 1 using a compound of formula A:
or a pharmaceutically acceptable salt thereof, wherein:
X is H 2 or O;
Y is N, CH, C—(C 1-6 alkyl), or O;
R 9a is selected from the group consisting of H, optionally substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cyclolkyl, or C(═O)cycloalkyl;
L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N—C 1-4 alkyl, N—C 1-4 cycloalkyl, —NH—C 1-4 alkylene, —N(C 1-4 alkyl)-C 1-4 alkylene, —N—C 1-4 alkylene-cycloalkyl, N—C 1-4 alkylene-heterocycloalkyl, N—C 1-4 alkylene-aryl, N—C 1-4 alkylene-heteroaryl, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-4 alkylene, C(═O)N(C 1-4 alkyl)-C 1-4 alkylene SO 2 , SO 2 NH, SO 2 N—C 1-4 alkyl, SO 2 N—(C 1-4 alkyl)-(C 1-4 alkylene), OC(═O)—NH, OC(═O)—N—C 1-4 alkyl, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl), SO 2 NH—(C 1-4 alkylene, SO 2 N(C 1-4 alkyl)-(C 1-4 alkylene), SO 2 N(C 1-4 alkylene-aryl), SO 2 N(C 1-4 alkylene-heteroaryl),
L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted benzyl; and
R 11a is H or C 1-6 alkyl.
20 . The method of claim 19 , wherein:
R 9a is —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe, or CH 2 CH 2 OH; R 11a is H or methyl; L c is absent or is C 1-4 alkylene, NH, N(C 1-4 alkyl), N(C 1-4 alkyl)-C 1-4 alkylene, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-4 alkylene, OC(═O)—NH, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl), or
L d is H, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, hydroxy, methoxy, cyclopropyl, cyclobutyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-toluyl, 3-toluyl, 4-toluyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl 4-trifluoromethylphenyl, naphthyl, imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
21 . The method of claim 19 , wherein:
X is H 2 or O; Y is Nor CH,; and R 11a is H or methyl.
22 . The method of claim 1 using a compound of formula A1:
or a pharmaceutically acceptable salt thereof, wherein:
X is H 2 or O;
R 9a is H or C 1-4 alkyl;
R 11a is H or C 1-4 alkyl;
L c is absent or is C 1-3 alkylene, C(═O), C(═O)NH, C(═O)NH—C 1-3 alkylene, or SO 2 C 1-3 alkylene; and
L d is NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.
23 . The method of claim 22 , wherein:
R 9a is H, Me, Et, Pr, butyl, or isopropyl; R 11a is H or Me; L c is CH 2 , CH 2 CH 2 , C(═O)NH, C(═O), C(═O)NHCH 2 , or SO 2 CH 2 ; and L d is N(CH 3 ) 2 , NHCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, phenyl, naphthalenyl, imidazolyl, pyrimidinyl, or pyridinyl, wherein phenyl, imidazolyl, pyrimidinyl, and pyridinyl are each independently and optionally substituted with F, Cl, Br, Me, OMe, or CF 3 .
24 . The method of claim 1 using a compound of formula A2:
or a pharmaceutically acceptable salt thereof, wherein:
R 9a is H or C 1-4 alkyl;
L c is C 1-3 alkylene, C(═O), C(═O)NH, C(═O)NH—C 1-3 alkylene, SO 2 , or SO 2 C 1-3 alkylene; and
L d is OH, NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , 6-10 membered aryl or 5-10 membered heteroaryl, wherein the aryl and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.
25 . The method of claim 24 , wherein
R 9a is H, Me, Et, Pr, butyl, or isopropyl; L c is CH 2 , CH 2 CH 2 , C(═O), C(═O)NH, C(═O)NHCH 2 , SO 2 , or SO 2 CH 2 ; and L d is OH, N(CH 3 ) 2 , NHCH(CH 3 ) 2 , phenyl, or pyridinyl, wherein phenyl and pyridinyl are each independently and optionally substituted with F, Cl, Br, Me, OMe, or CF 3 .
26 . The method of claim 1 using a compound of formula B:
or a pharmaceutically acceptable salt thereof, wherein:
X is H 2 or O;
R 9a is selected from the group consisting of H, optionally substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cyclolkyl, C(═O)cycloalkyl, or C(═O)NH-aryl;
L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N—C 1-4 alkyl, N—C 1-4 cycloalkyl, —NH—C 1-4 alkylene, —N(C 1-4 alkyl)-C 1-4 alkylene, —N—C 1-4 alkylene-cycloalkyl, N—C 1-4 alkylene-heterocycloalkyl, N—C 1-4 alkylene-aryl, N—C 1-4 alkylene-heteroaryl, C(═O), C(═O)O—C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-4 alkylene, C(═O)N(C 1-4 alkyl)-C 1-4 alkylene SO 2 , SO 2 NH, SO 2 N—C 1-4 alkyl, SO 2 N—(C 1-4 alkyl)-(C 1-4 alkylene), OC(═O)—NH, OC(═O)—N—C 1-4 alkyl, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl), SO 2 NH—(C 1-4 alkylene, SO 2 N(C 1-4 alkyl)-(C 1-4 alkylene), SO 2 N(C 1-4 alkylene-aryl), SO 2 N(C 1-4 alkylene-heteroaryl),
L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted benzyl; and
R 11a is H or C 1-6 alkyl.
27 . The method of claim 26 , wherein:
R 9a is —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe, or CH 2 CH 2 OH; R 11a is H or methyl; L c is absent or is C 1-4 alkylene, NH, N—C 1-4 alkyl, or —N(C 1-4 alkyl)-C 1-4 alkylene; and L d is H, C 1-6 alkyl, or C 1-4 cycloalkyl.
28 . The method of claim 26 , wherein:
X is H 2 or O; R 9a is —H or methyl; and R 11a is H or methyl.
29 . The method of claim 9 , wherein L a is CH 2 CH 2 or CH 2 CH 2 CH 2 , wherein one methylene unit of L a can optionally be replaced by oxo.
30 . The method of claim 29 , wherein:
L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 , CH 2 COCH 2 ; L b is absent, or is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; L c is absent or is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N—C 1-6 alkyl, N—C 1-6 cycloalkyl, —NH—C 1-6 alkylene, —NH—C 1-6 alkylene-heteroarylene, —N(C 1-6 alkyl)-C 1-6 alkylene, —N—C 1-6 alkylene-cycloalkyl, N—C 1-6 alkylene-heterocycloalkyl, N—C 1-6 alkylene-aryl, N—C 1-6 alkylene-heteroaryl, C(═O), C(═O)O—, OC(O)—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N—C 1-6 alkyl, OC(═O)—NH, OC(═O)—N-alkyl, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH—(C 1-6 alkylene, SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl),
and
L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
31 . The method of claim 29 , wherein:
L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 , CH 2 COCH 2 ; L b is C 3-6 cycloalkyl or 5-6 membered heterocycloalkyl; L c is absent; and L d is H, OH, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl.
32 . The method of claim 29 , wherein:
L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 , CH 2 COCH 2 ; L b is absent; L c is absent; and L d is pyrrolidinyl, oxazolyl,
where indicates a point of attachment.
33 . The method of claim 29 , wherein:
L a is CH 2 CH 2 , CH 2 CH 2 CH 2 , COCH 2 , COCH 2 CH 2 , CH 2 COCH 2 ; L b is absent, L c is N(C 1-6 alkyl), NH, N—C 1-6 alkyl, N—C 1-6 cycloalkyl, —NH—C 1-6 alkylene, —NH—C 1-6 alkylene-heteroarylene, —N(C 1-6 alkyl)-C 1-6 alkylene, —N—C 1-6 alkylene-cycloalkyl, N—C 1-6 alkylene-heterocycloalkyl, N—C 1-6 alkylene-aryl, or N—C 1-6 alkylene-heteroaryl; and L d is H, OH, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
34 . The method of claim 33 , wherein:
L a L b is CH 2 CH 2 CH 2 ; and L c L d is NH 2 , NH-Me, NH-Et, NH-isopropyl, NH-cyclopropyl, NH-cyclobutyl, NH-cyclopentyl, N(Me) 2 , N(Et) 2 , N(Me)(Et), N(Me)-cyclopropyl, N(Me)-cyclobutyl, N(Me)-cyclopentyl, N(Me)CH 2 -imidazolyl, N(Me)(iPr), N(Me)(tBu), NH-cyclopropyl, NH-oxazolyl, NH-pyrimidinyl, NH-pyridyl, NHCH 2 -cyclopropyl, NHCH 2 -oxazolyl, NHCH 2 -pyrimidinyl, NHCH 2 -pyridyl, NHCH 2 -quinazolinyl, NHCH 2 -quinolinyl, or NHCH 2 -oxadiazolene-phenyl.
35 . The method of claim 29 , wherein:
L a is CH 2 CH 2 CH 2 ; L b is absent; L c is absent; and L d is OH or alkoxy.
36 . The method of claim 29 , wherein:
L a is CH 2 CH 2 CH 2 , L b is absent; L c is N(Me), N(Et), N(Me)(CH 2 ), or NH; and L d is H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolyl, imidazolyl.
37 . The method of claim 29 , wherein:
L a is CH 2 CH 2 CH 2 ; L b is absent; L c is CO, C(═O)O—, OC(═O)—NH, C(═O)NH, or C(═O)NHCH 2 ; and L d is H, C 1-6 alkyl, or optionally substuted aryl or heteroaryl.
38 . The method of claim 29 , wherein:
L a L b is CH 2 CH 2 CH 2 ; and L c L d is O—C(═O)NH-phenyl, or
39 . The method of claim 29 , wherein:
L a is CH 2 CH 2 CH 2 : L b is optionally substituted cycloalkyl or heterocycloalkyl; L c is absent; and L d is H, OH, C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
40 . The method of claim 29 , wherein:
L a is CH 2 CH 2 CH 2 ; L b is absent; L c is absent; and L d is selected from the group consisting of, pyrrolidinyl, piperidinyl, piperazinyl,
41 . The method of claim 29 , wherein:
L a is CH 2 CH 2 CH 2 ; L b is absent; L c is absent; and L d is H, methyl, trifluoromethyl, phenyl, pyridyl, pyrimidinyl, OH,
where indicates a point of attachment.
42 . The method of claim 29 , wherein:
L a is COCH 2 CH 2 ; L b is absent; L c is absent; and L d is phenyl, pyridyl, pyrimidinyl, OH,
where indicates a point of attachment.
43 . The method of claim 29 , wherein:
L a is COCH 2 CH 2 ; L b is absent; L c is C 1-6 alkylene, C 1-6 alkylene-N(C 1-6 alkyl), NH, N—C 1-6 alkyl, N—C 1-6 cycloalkyl, —NH—C 1-6 alkylene, —N(C 1-6 alkyl)-C 1-6 alkylene, —N—C 1-6 alkylene-cycloalkyl, N—C 1-6 alkylene-heterocycloalkyl, N—C 1-6 alkylene-aryl, N—C 1-6 alkylene-heteroaryl, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-6 alkylene, C(═O)N(C 1-6 alkyl)-C 1-6 alkylene SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N—C 1-6 alkyl, OC(═O)—NH, OC(═O)—N-alkyl, SO 2 , SO 2 C 1-6 alkylene, SO 2 NH, SO 2 N(C 1-6 alkyl), SO 2 NH—(C 1-6 alkylene, SO 2 N(C 1-6 alkyl)-(C 1-6 alkylene), SO 2 N(C 1-6 alkylene-aryl), SO 2 N(C 1-6 alkylene-heteroaryl),
and
L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl.
44 . The method of claim 29 , wherein:
L a is COCH 2 CH 2 ; L b is absent; L c is NH or NHCH 2 ; and L d is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl.
45 . The method of claim 29 , wherein:
L a is COCH 2 CH 2 ; L b is absent; L c is NH or NHCH 2 ; and L d is optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted oxazolyl, optionally substituted cyclobutyl.
46 . The method of claim 1 using a compound of formula C:
or a pharmaceutically acceptable salt thereof, wherein:
Z is H 2 or O;
R 9a is selected from the group consisting of H, optionally substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cyclolkyl, C(═O)cycloalkyl, or C(═O)NH-aryl;
L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N—C 1-4 alkyl, N—C 1-4 cycloalkyl, —NH—C 1-4 alkylene, —NH—C 1-6 alkylene-heteroarylene, —N(C 1-4 alkyl)-C 1-4 alkylene, —N—C 1-4 alkylene-cycloalkyl, N—C 1-4 alkylene-heterocycloalkyl, N—C 1-4 alkylene-aryl, N—C 1-4 alkylene-heteroaryl, C(═O), C(═O)O— C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-4 alkylene, C(═O)N(C 1-4 alkyl)-C 1-4 alkylene SO 2 , SO 2 NH, SO 2 N—C 1-4 alkyl, SO 2 N—(C 1-4 alkyl)-(C 1-4 alkylene), OC(═O)—NH, OC(═O)—N—C 1-4 alkyl, SO 2 , SO 2 C 1-4 alkylene, SO 2 NH, SO 2 N(C 1-4 alkyl), SO 2 NH—(C 1-4 alkylene, S) 2 N(C 1-4 alkyl)-(C 1-4 alkylene), SO 2 N(C 1-4 alkylene-aryl), SO 2 N(C 1-4 alkylene-heteroaryl),
L d is H, C 1-6 alkyl, OH, alkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl optionally substituted aryl, optionally substituted heteroaryl, optionally substituted benzyl; and
R 11a is H or C 1-6 alkyl.
47 . The method of claim 46 , wherein:
R 9a is —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(═O)—NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe, or CH 2 CH 2 OH; L c is absent or is C 1-4 alkylene, C 1-4 alkylene-N(C 1-4 alkyl), NH, N(C 1-4 alkyl), N(C 1-4 cycloalkyl), —NH—C 1-4 alkylene, —N(C 1-4 alkyl)-C 1-4 alkylene, C(═O), C(═O)O—, C(═O)NH, C(═O)N-alkyl, C(═O)NH—C 1-4 alkylene, C(═O)N(C 1-4 alkyl)-C 1-4 alkylene, or OC(═O)—NH; L d is H, C 1-6 alkyl, OH, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-12 aryl, optionally substituted 5-10 membered heteroaryl.
48 . The method of claim 46 , wherein:
Z is H 2 or O; R 9a is —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, acetyl, C(═O)—NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, or CH 2 CH 2 OH; and R 11a is H or methyl.
49 . The method of claim 1 using a compound of formula C1:
or a pharmaceutically acceptable salt thereof, wherein:
R 9a is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cyclolkyl, C(═O)cycloalkyl, and C(═O)NH-aryl;
L c is NH, NH—C 1-4 alkylene, NH—C 1-4 alkylene-(5-10 membered heteroarylene), C(═O)O—, C(═O)NH, or OC(═O)—NH; and
L d is C 3-6 cycloalkyl, 6-10 membered aryl, or 5-10 memebred heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.
50 . The method of claim 49 , wherein
R 9a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(═O)—NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe, or CH 2 CH 2 OH; L c is NH, NH—CH 2 , NH—CH 2 -(5-6 membered heteroarylene), C(═O)O—, C(═O)NH, or OC(═O)—NH; and L d is C 3-6 cycloalkyl, phenyl, or 5-10 memebred heteroaryl.
51 . The method of claim 1 using a compound of formula C2:
or a pharmaceutically acceptable salt thereof, wherein:
R 9a is selected from the group consisting of H, substituted C 1-6 alkyl, C 1-6 alkylene-OH, C 1-6 alkylene-O—C 1-6 alkyl, C(═O)C 1-6 alkyl, C 1-6 alkylene-cyclolkyl, C(═O)cycloalkyl, and C(═O)NH-aryl;
L c is absent or is NH, or NH—C 1-4 alkylene; and
L d is OH, C 3-6 cycloalkyl, 5-10 membered heterocycloalkyl, 6-10 membered aryl, or 5-10 memebred heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently and optionally substituted with halo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.
52 . The method of claim 51 , wherein
R 9a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, acetyl, C(═O)—NH-phenyl, C(═O)-ethyl, C(═O)-cyclopropyl, CH 2 -cyclobutyl, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 OMe, or CH 2 CH 2 OH; L c is absent or is NH or NH—CH 2 ; and L d is OH, C 3-6 cycloalkyl, phenyl, 5-6 membered heteocycloalkyl, or 6-10 memebred nitrogen containing heteroaryl.
53 . The method of claims 1-52 , wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from compounds depicted in Table A and Table B.
54 . A compound or pharmaceutically acceptable salt thereof which is depicted in Table B.
55 . A pharmaceutical composition comprising a compound of claim 54 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
56 . The method claims 1-53 , wherein the compound is admistered as a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
57 . The method of claims 1-53 wherein the genetic disease is associated with a premature termination codon mutation.
58 . A method for treating a subject having a genetic disease is associated with a premature termination codon mutation, the method comprising:
administering an effective amount of a compound as recited in claim 1-53 .
59 . The method of any of claims 1-53 , wherein the compound is administered to the subject alone or in any combination with an agent selected from the group consisting of aminoglycoside, potentiator, corrector, amplifier, and any combinations thereof.
60 . The method of any of claims 1-53 , wherein the genetic disease is selected from the group consisting of cystic fibrosis (CF), muscular dystrophy (Duchenne (DMD), Becker (BMD), congenital), spinal muscular atrophy (SMA), ataxia-telangiectasia, mucopolysaccharidosis type 1 (MPS1) (Hurler syndrome), hemophilia (A & B), Usher syndrome (Retinitis pigmentosa, X-linked retinitis pigmentosa), Tay-Sachs, factor VII deficiency, familial atrial fibrillation, Hailey-Hailey disease, McArdle disease, mucopolysaccharidosis, nephropathic cystinosis, polycystic kidney disease, Rett syndrome, cystinosis, severe epidermolysis bullosa, dravet syndrome, X-linked nephrogenic diabetes insipidus (XNDI), cancer, beta-thalassemia, obesity, epidermolysis bullosa (EB), and familial ademonous polypsis (FAP).
61 . The method of any of claims 1-53 wherein the genetic disease is selected from the group consisting of cystic fibrosis (CF), muscular dystrophy (Duchenne (DMD), Becker (BMD), congenital), spinal muscular atrophy (SMA), hemophilia (A & B), Usher syndrome (Retinitis pigmentosa, X-linked retinitis pigmentosa), mucopolysaccharidosis, nephropathic cystinosis, Rett syndrome, cancer, Beta-thalassemia, obesity, epidermolysis bullosa (EB), and familial ademonous polypsis (FAP).
62 . The method of any of claims 1-53 wherein the genetic disease is selected from the group consisting of cystic fibrosis, epidermolysis bullosa, severe epidermolysis bullosa, dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, and familial ademonous polypsis.
63 . The method of 62, wherein the genetic disease is cystic fibrosis.
64 . The method of 62, wherein the genetic disease is recessive dystrophic epidermolysis bullosa.
65 . The method of 62, wherein the genetic disease is junctional epidermolysis bullosa.
66 . The method of 62, wherein the genetic disease is familial ademonous polypsis.
67 . A process for preparing a compound as defined in claims 1-53 , comprising:
(a) coupling a compound of formula P-1 with a compound of formula P-4 to provide a compound of formula P-5.
and
(b) cyclizing a compound of formula P-5 and subsequently deprotecting to provide a compound of formula I or a salt thereof:Cited by (0)
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